Biologically highly sensitive active materials such as certain pharmaceuticals, peptides, proteins, enzymes and vaccines are preferably used parenterally as injection solutions. Many of these active materials have a short biological half-life or are not very active when applied in solution (vaccines). This means, that a continuous or pulse-like release of active material (long term release) represents an unavoidable prerequisite for a successful therapeutic or preventive treatment. Such prolonged release of active material can be achieved through incorporating the active material, for example, into a biodegradable release system. Such release systems can be produced in the form of microcapsules or implant rods. Biodegradable microcapsules have proved to be especially useful in the past, because these particles can be easily administered parenterally with common injection needles. Known biodegradable pharmaceutical release systems are based on polyesters of lactic acid and glycolic acid (D. H. Lewis, Controlled release of bioactive agents from lactide/glycolide polymers, in: Biodegradable polymers as drug delivery systems, M. Chasin, and R. Langer (Eds.), M. Dekker, New York, 1990, pp. 1-41).
For the production of microcapsules from polyesters, such as poly(lactides) and poly(lactide-co-glycolides), three main processes are known: the coacervation (phase separation), e.g. through addition of a non-solvent, solvent evaporation, or solvent extraction from an oil-in-water dispersion, and spray drying (R. Jalil et al., J. of Micro-encapsulation 7,297-325, (1990)). Common to all of these processes is the requirement of an organic polymer solvent, which is removed again for the most part through the process. Because the complete removal of the solvent from the polymer is not possible, residual solvent always remains in the microcapsules, lying in the range of 0.01-10% (G. Spenlehauer et al., Biomaterials 10, 557-563, (1989)); D. H. Lewis et al., PCT WO 89/03678). The solvents mainly described until now for the three processes above are not biodegradable and in part are extremely toxic or environmentally harmful, e.g. methylene chloride, chloroform, benzene, tetrahydrofuran, acetonitrile, fluorochlorohydrocarbons and others, which compromise the advantages of these biodegradable release systems.
For illustration, according to the U.S. Pat. No. 5,066,436 microcapsules are produced through coacervation, which are contaminated with such organic solvents to a large extent. In addition to the polymer solvent, other organic solvents are used for the actual phase separation, for the hardening and washing of the microcapsules. Moreover, the microcapsules produced this way are relatively large and agglomerate easily during the production process which additionally aggravates the removal of residual solvent.
The disadvantages connected with the solvent evaporation or extraction methods lie in the previously mentioned toxicologically not completely harmless residual solvents of the microcapsules. On the other hand, these particular methods show the inherent difficulty that water soluble active materials such as certain pharmaceuticals, peptides, proteins, enzymes, and vaccines are lost through the aqueous dispersion phase and, therefore, escape partial or complete encapsulation.
Spray drying is a known, simple and quick process for the production of biodegradable microcapsules. The difficulty of producing spherical and not porous particles of the biodegradable lactic and glycolic acid polymers has been repeatedly pointed out. With the poly (D,L-lactic acid) dissolved in methylene chloride, very irregular microcapsules are obtained with an irregular surface and a high proportion of fibrous material (R. Bodmeier et al., J. Pharm. Pharmacol. 40, 754-757 (1988)). According to the European Patent Application A1 315,875 copolymers of lactic and glycolic acid (PLGA) cannot be processed into microcapsules via spray drying. These copolymers are, however especially interesting as matrix or wall material, because they break down more quickly in the organism than the pure homopolymers of lactic and glycolic acid. It has been described that the PLGA-polymers, especially PLGA composed of 50% of each lactic and glycolic acid (PLGA 50:50), give release of the active material over 3-4 weeks, which for example for hormonal and enzyme therapy represents a desirable dosing interval.
A further difficulty with spray drying for microencapsulation arises from the properties of the substance to be encapsulated. Substances, which are soluble in polymer solution (e.g. in methylene chloride), are usually built into microcapsules with relatively high efficiency and homogenous distribution (high `content uniformity`). In contrast, the microencapsulation of substances which are insoluble in polymer solution is more difficult as for example for certain pharmaceuticals, peptides, proteins, enzymes and vaccines. If these active materials are suspended in the organic polymer solution in a micronized form, only an unsatisfactory incorporation efficiency is often achieved, which is strongly dependent on the fineness of the active material. For this reason, water soluble active materials are often first dissolved in water, and the aqueous solution of active material solution is then dispersed in the polymer solution (water-in-oil dispersion). With the common known solvents, only unsatisfactory water-in-oil dispersions can be produced which prove to have insufficient fineness and physical stability. The result is a quick coalescence of the dispersed, aqueous phase (coalescence), and connected with this, a poor encapsulation efficiency. For this reason, it has been repeatedly observed that micro-encapsulated protein is released within 1-3 days. This is traced back in general to a high proportion of insufficiently encapsulated active material and high microcapsule porosity (H. T. Wang et al., Biomaterials, 11, 679-685 (1990)). In addition, water miscible solvents such as acetone, tetrahydrofuran, dioxane, acetonitrile and other cannot be used because this miscibility may lead to precipitation or aggregation of the active material and/or the polymer.